An overview of NIDA’s current medications pipeline for the treatment of opioid use disorder (OUD) is presented. OUD and its consequences are a major public health concern with a devastating opioid use and overdose crisis in the US. Misuse and abuse of prescription opioids (including fentanyl), heroin and others are associated with a high burden of morbidity and mortality. It has been reported that around 50 million adults suffered from chronic pain in 2019. Opioids that are often prescribed for their treatment can lead to opioid misuse and OUD. Approximately 2.4 million Americans have OUD and many started their addiction with prescribed opioids. One of the most devastating consequences of opioid misuse is opioid overdose, which can produce respiratory depression and death. Drug overdose is the leading cause of accidental death in the US, with an estimation of 70,630 deaths in 2019; 49,860 of those being overdose deaths related to opioids. Medication-assisted treatment is a recommended treatment for individuals with OUD. Although there are safe and effective pharmacotherapies for opioid use disorders and to prevent/reverse overdose, their use has some limitation or they are largely underutilized. Methadone and buprenorphine are approved by the FDA to treat OUD but long term efficacy and treatment adherence are sub-optimal. As mu-opioid full and partial agonists, respectively, methadone and buprenorphine have abuse liability and there is well-documented misuse, abuse, and diversion of these products, particularly in high-risk populations such as those with OUD. Naltrexone, an opioid antagonist, is approved by the FDA to prevent opioid use relapse in people with no physical dependence to opioids but initiation and adherence to treatment are low. Naloxone, an opioid antagonist, is approved to reverse opioid overdose but it has a short action, may precipitate opioid withdrawal, and put the person at risk of overdose. And finally, Lofexidine, an alpha-2-adrenergic agonist, is approved for the treatment of opioid withdrawal in adults but it is not approved to treat pregnant women and neonatal opioid withdrawal syndrome. Other medications such as gabapentin, pregabalin, cannabinoids, ketamine, and ultra-low doses of oral naltrexone, as well as rapid opioid withdrawal under anesthesia, have been investigated, but the results are inconclusive. So despite the availability of multiple medications for OUD, the ongoing overdose crisis indicates the need for improved treatment options. To address this issue, in 2018, the National Institutes of Health (NIH) established a set of research priorities reflecting urgent unmet needs across areas of promising scientific opportunity, and concrete strategies capable of providing rapid and durable solutions to the opioid crisis known as Helping End Addiction Long Term or NIH HEAL Initiative. One of NIDA’s major role in the HEAL Initiative was to support studies to accelerate the discovery and development of novel medications to treat the opioid addiction cycle. This program is including the development of new formulations of existing medications, stronger and longer-duration formulations to counteract opioid overdose, interventions for respiratory depression, novel medications to treat withdrawal, craving, progression and relapse, and new medication targets to treat OUD and improve the quality of life of people recovering from OUD. These efforts are described in this overview and do not include other therapies such as devices, digital therapeutics or behavioral approaches. 

Learning Objectives:

1.    Explain current limitations of marketed FDA-approved therapies for the treatment of OUD.

2.    Identify drug candidates with novel mechanisms (not targeting the opioid receptor) currently in development for the treatment of OUD.

3.    Identify advantages of potential new formulations of already FDA-approved therapies.